T cells bearing alphabeta T cell receptors react with antigen in the form of peptides bound to major histocompatibility complex proteins (MHC). This reaction is crucial to the ability of T cells to orchestrate destruction of invading organisms. It is also involved in graft rejection and in T cell attacks on the tissues of their own host in autoimmune disease. Several aspects of T cell reaction with MHC are not understood. The projects in this application will study two of these aspects. The first set of experiments will study the ways in which T cells are selected to react with peptides bond to MHC in the thymus. A major focus of these experiments will be the role of the peptides bound to MHC. Mice will be created in which a single peptide is firmly bound to an MHC protein, and the ability of this MHC/single peptide combination to select T cells studied. The second set of experiments will investigate the relationship between T cell receptors and MHC. It is thought that the two sets of proteins may have an intrinsic affinity for each other. Experiments proposed here will try to find out if this is so. T cells from the MHV/single peptide mice, which are very reactive with MHC proteins, will be used to study the phenomenon.